Protein–Ligand Interactions: Thermodynamic Effects Associated with Increasing Nonpolar Surface Area

Abstract

Thermodynamic parameters were determined for complex formation between the Grb2 SH2 domain and Ac–pTyr–Xaa–Asn derived tripeptides in which the Xaa residue is an α,α-cycloaliphatic amino acid that varies in ring size from 3- to 7-membered. Although the 6- and 7-membered ring analogs are approximately equipotent, binding affinities of those having 3- to 6-membered rings increase incrementally with ring size because increasingly more favorable binding enthalpies dominate increasingly unfavorable binding entropies, a finding consistent with an enthalpy-driven hydrophobic effect. Crystallographic analysis reveals that the only significant differences in structures of the complexes are in the number of van der Waals contacts between the domain and the methylene groups in the Xaa residues. There is a positive correlation between buried nonpolar surface area and binding free energy and enthalpy, but not with ΔCp. Displacing a water molecule from a protein-ligand interface is not necessarily reflected in a favorable change in binding entropy. These findings highlight some of the fallibilities associated with commonly held views of relationships of structure and energetics in protein-ligand interactions and have significant implications for ligand design.

Natural Products and Their Mimics as Targets of Opportunity for Discovery

“…208 In order to investigate the energetic origin of these potency enhancements, we prepared 362 ( n = 1–4) and determined the binding entropies and enthalpies for their complexation with the Grb2 SH2 domain. 209 In accord with the results of Garcia-Echeverría, we found that the binding affinities increased upon the addition of methylene groups (see Figure 21). This trend resulted from increasingly more favorable binding enthalpies that dominated less favorable binding entropies.…”

“…209 The only significant differences in these complexes are in the number of van der Waals contacts between the domain and the methylene groups ring at the pY+1 position. There is thus a positive correlation between buried nonpolar surface area and binding free energy and enthalpy, but not entropy as might have been expected.…”

Protein-Peptide Interactions Revolutionize Drug Development

“…The Stat3 SH2 recognition sequence pYXXQ (where pY is the phosphotyrosine and X is any residue) was modified into a lead peptidomimetic, nanomolar affinity was attained [68]. The structure of Grb2 SH2 domain in complex with a pYXN-derivative [139] is shown in Figure 5.…”

Multiple binding modes for palmitate to barley lipid transfer protein facilitated by the presence of proline 12

“…In other cases there is much more promiscuity, with a variety of ligands being accommodated, for example, in a hydrophobic cavity within a protein. [6][7][8] Both X-ray crystallography and NMR techniques have the potential to determine in detail the structures of protein-ligand complexes. However, there can be limitations to these structure determination methods, particularly if the ligand retains a degree of mobility when it is bound or if multiple binding modes are adopted by a given ligand.…”